Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting nerve cells in the brain and spinal cord. Pridopidine is a compound currently under investigation for various neurological conditions, including ALS.
Understanding ALS
ALS is a neurodegenerative disorder characterized by the progressive loss of motor neurons, which are nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing. As these motor neurons degenerate and die, they cease sending messages to the muscles, leading to muscle weakness, twitching, and wasting. This progressive loss of muscle control eventually affects a person’s ability to walk, talk, chew, swallow, and breathe.
The disease can begin with symptoms like muscle stiffness, twitches, and weakness in the arms or legs (limb-onset), or difficulty speaking or swallowing (bulbar-onset). While some approved medications may help prolong survival or manage symptoms, no known treatment currently stops or reverses ALS progression.
Pridopidine as a Therapeutic Agent
Pridopidine is an oral investigational drug that acts as a selective agonist of the sigma-1 receptor (S1R). The S1R is a protein found throughout the brain and central nervous system, including the spinal cord and brain stem, areas particularly relevant to neurodegenerative diseases. Activation of S1R by pridopidine is believed to support neuronal health by influencing several cellular mechanisms.
Research suggests that S1R modulation by pridopidine can enhance the clearance of toxic proteins, increase cellular energy production, and reduce cellular stress and inflammation. These actions are beneficial for neuron function and survival, which are impaired in neurodegenerative conditions. Pridopidine has also been investigated in other neurological disorders, such as Huntington’s disease.
Clinical Investigation in ALS
Pridopidine’s potential for ALS has been investigated in clinical trials, notably within the HEALEY ALS Platform Trial. This Phase 2/3, multicenter, randomized, double-blind trial evaluated the effects of pridopidine on ALS progression. Participants received either 45 mg of pridopidine twice daily or a matching placebo for 24 weeks.
The primary goal of the pridopidine arm was to assess its impact on disease progression, measured by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R). While the trial did not meet its primary endpoint in the overall participant group, beneficial effects were observed in measures of speech, including improved speaking rate and articulation rate.
Further analysis indicated that in a subgroup of participants with definite ALS and those in earlier stages of the disease (symptom onset within 18 months), pridopidine showed favorable trends in ALSFRS-R progression and respiratory function. This subgroup also demonstrated a slowing of decline in dyspnea, a symptom related to difficulty breathing. The safety profile of pridopidine showed good tolerability with adverse events comparable to placebo.
Current Status and Patient Outlook
Pridopidine currently holds Orphan Drug designation for ALS in both the United States and Europe, a status granted to encourage the development of therapies for rare and serious diseases. Despite not meeting the primary endpoint in the overall HEALEY ALS Platform Trial, the encouraging results observed in specific subgroups, particularly those with earlier disease and bulbar involvement, have prompted further investigation.
Prilenia Therapeutics, the developer of pridopidine, is planning to initiate a global Phase 3 study for ALS, building on the findings from the HEALEY trial. While pridopidine has not yet received marketing approval from regulatory agencies, an Expanded Access Program (EAP) is underway in the U.S., allowing some ALS patients not eligible for clinical trials to access the investigational therapy. This ongoing research and EAPs explore pridopidine’s potential role in the future treatment landscape for ALS.